RT Journal Article
SR Electronic
T1 Acquired Resistance to Alectinib in ALK-Rearranged Lung Cancer Due to ABCC11/MRP8 Overexpression in a Clinically Paired Resistance Model
JF Molecular Cancer Therapeutics
JO Mol Cancer Ther
FD American Association for Cancer Research
SP molcanther.0649.2019
DO 10.1158/1535-7163.MCT-19-0649
A1 Funazo, Tomoko Yamamoto
A1 Tsuji, Takahiro
A1 Ozasa, Hiroaki
A1 Furugaki, Koh
A1 Yoshimura, Yasushi
A1 Oguri, Tetsuya
A1 Ajimizu, Hitomi
A1 Yasuda, Yuto
A1 Nomizo, Takashi
A1 Sakamori, Yuichi
A1 Yoshida, Hironori
A1 Kim, Young Hak
A1 Hirai, Toyohiro
YR 2020
UL http://mct.aacrjournals.org/content/early/2020/03/26/1535-7163.MCT-19-0649.abstract
AB Alectinib is used as a first-line treatment for anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC). Whereas other ALK inhibitors have been reported to be involved in resistance to ATP binding cassette (ABC) transporters, no data are available regarding the association between resistance to alectinib and ABC transporters. To investigate whether ABC transporters contribute to alectinib resistance, ABC transporter expression in alectinib-resistant cell lines derived from a patient with ALK-rearranged NSCLC and from H2228 lung cancer cells was evaluated and compared with that in each parent cell type. ATP-binding cassette subfamily C member 11 (ABCC11) expression was significantly increased in alectinib-resistant cell lines compared to that in alectinib-sensitive lines. ABCC11 inhibition increased sensitivity to alectinib in vitro. ABCC11-overexpressing cells were established by transfection of an ABCC11 expression vector into H2228 cells, while control cells were established by transfecting H2228 cells with an empty vector. ABCC11-overexpressing cells exhibited decreased sensitivity to alectinib compared with that of control cells in vitro. Moreover, the tumor growth rate following alectinib treatment was higher in ABCC11-overexpressing cells than that in control cells in vivo. In addition, the intracellular alectinib concentration following exposure to 100 nM alectinib was significantly lower in the ABCC11-overexpressing cell line compared with that in control cells. This is the first preclinical evidence showing that ABCC11 expression may be involved in acquired resistance to alectinib.